Hereditary Nonhemolytic Disorders Associated with Red Blood Cell Enzyme Deficiency

Hereditary Nonhemolytic Blood Disorders Associated with Red Blood Cell Enzyme Deficiency 

Hereditary deficiency of LDH-B was first reported by Kitamura et al. in 1970 (K21). Since then, this enzyme deficiency has been discovered in at least five families in Japan. There were no clinical symptoms in these cases. On the other hand, LDH-A deficiency was associated with an exertional rhabdomyolysis and myoglobinuria after severe exercise (K15). One Japanese and one Italian with LDH-A deficiency showed the typical skin rash. To date, nine LDH-A variants have been analyzed at the molecular level, and four missense mutations, one nonsense mutation, one frameshift mutation due to a single base insertion, and three gene deletions have been elucidated (K16, M5). Missense mutations have also been identified in LDH-B deficiency (M6). 

Two forms of this enzyme are known, a membrane-bound form mainly found in microsomes of all cells and a soluble form present in red blood cells. Structurally, the soluble form with 275 amino acid residues lacks a hydrophobic segment at the NH2 terminus which is present in the membrane-bound enzyme with 300 amino acid residues. Both isoforms are produced by a single gene on chromosome 22 (T17,Y4). 

Hereditary methemoglobinemia is classified into three types a red blood cell type (type I), a generalized type (type II), and a blood cell type (type HI). Enzyme deficiency of type I is limited to red blood cells, and these patients show only the diffuse, persistent, slate-gray cyanosis not associated with cardiac or pulmonary disease. In type II, the enzyme deficiency occurs in all cells, and patients of this type have a severe neurological disorder with mental retardation that predisposes them to early death. Patients with type III show symptoms similar to those of patients with type I. The precise nature of type III is not clear, but decreased enzyme activity is observed in all cells (M9). It is considered that uncomplicated hereditary methemoglobinemia without neurological involvement arises from a defect limited to the soluble cytochrome b5 reductase and that a combined deficiency of both the cytosolic and the microsomal cytochrome b5 reductase occurs in subjects with mental retardation. Up to now, three missense mutations in type I and three missense mutations, two nonsense mutations, two in-frame 3-bp deletions, and one splicing mutation in type n have been identified (M3, M8, M31). 

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